Submissions for variant NM_000492.4(CFTR):c.1826A>G (p.His609Arg)

gnomAD frequency: 0.00001  dbSNP: rs397508310

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000577469	SCV000924271	pathogenic	Cystic fibrosis	2017-12-08	reviewed by expert panel	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000577469	SCV000696876	pathogenic	Cystic fibrosis	2017-02-28	criteria provided, single submitter	clinical testing	Variant summary: The CFTR c.1826A>G (p.His609Arg) variant located in the P-loop containing nucleoside triphosphate hydrolase (via InterPro) causes a missense change involving a conserved nucleotide, which 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 119096 control chromosomes. Multiple publications cite the variant in affected individuals diagnosed with CF including both compound heterozygotes and 4 homozygous individuals, who are indicated to have a more severe phenotype than the compound heterozygous individuals. Although, no clinical diagnostic laboratories have cited this variant with a classification. In addition, LCA has classified additional missense variants surrounding the variant of interest in the pathogenic spectrum such as c.1837A>G (p.Ala613Thr VUS-possibly pathogenic), c.1841A>G (p.Asp614Gly pathogenic), and c.1853T>C (p.Ile618Thr VUS-possibly pathogenic), therefore, suggesting this region could be important for proper CFTR function. Taken together, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001757	SCV001159373	likely pathogenic	not specified	2018-07-29	criteria provided, single submitter	clinical testing	The CFTR c.1826A>G; p.His609Arg variant (rs397508310) has been reported in numerous individuals affected with cystic fibrosis, either in the homozygous state or in trans with another pathogenic variant (Keyeux 2003, McGinniss 2005, Moya-Quiles 2009, Ortiz 2017, Schrijver 2016, CFTR2 database). The variant is listed in ClinVar (Variation ID: 53398) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The histidine at residue 609 is moderately conserved, and computational algorithms (PolyPhen-2: damaging; SIFT: tolerated) predict conflicting effects of this variant on protein structure/function. Using a cell-based assay measuring CFTR-generated current, one study observed p.His609Arg variant activity at 2.2% of wildtype (Rareigh 2018). Based on available information, this variant is considered to be likely pathogenic. References: CFTR2 database: https://cftr2.org Keyeux G et al. CFTR mutations in patients from Colombia: implications for local and regional molecular diagnosis programs. Hum Mutat. 2003 Sep;22(3):259. McGinniss MJ et al. Extensive sequencing of the CFTR gene: lessons learned from the first 157 patient samples. Hum Genet. 2005 Dec;118(3-4):331-8. Moya-Quiles MR et al. CFTR H609R mutation in Ecuadorian patients with cystic fibrosis. J Cyst Fibros. 2009 Jul;8(4):280-1. Ortiz SC et al. Spectrum of CFTR gene mutations in Ecuadorian cystic fibrosis patients: the second report of the p.H609R mutation. Mol Genet Genomic Med. 2017 Nov;5(6):751-757. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Schrijver I et al. The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients: Implications for Molecular Diagnostic Testing. J Mol Diagn. 2016 Jan;18(1):39-50.
CFTR-France	RCV001009543	SCV001169638	pathogenic	Cystic fibrosis; CFTR-related disorder	2018-03-09	criteria provided, single submitter	curation	the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284132	SCV001469756	likely pathogenic	not provided	2020-01-15	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577469	SCV001578432	pathogenic	Cystic fibrosis	2024-09-12	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 609 of the CFTR protein (p.His609Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with congenital bilateral absence of the vas deferens and cystic fibrosis (PMID: 14685937, 16189704, 16963320, 19457724, 26708955). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53398). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000577469	SCV004000036	pathogenic	Cystic fibrosis	2023-04-17	criteria provided, single submitter	clinical testing	The p.H609R pathogenic mutation (also known as c.1826A>G), located in coding exon 14 of the CFTR gene, results from an A to G substitution at nucleotide position 1826. The histidine at codon 609 is replaced by arginine, an amino acid with highly similar properties. This mutation was initially reported as identified in one Italian cystic fibrosis (CF) chromosome; however, complete genotype and phenotype information was not provided (Padoan R et al. Acta Paediatr., 2002;91:82-7). This mutation was identified in the homozygous state in 4 individuals with CF from 3 Ecuadorian families; all 4 individuals has elevated sweat chloride levels and the parents in each family were confirmed carriers of this mutation. Three of these individuals had Pseudomonas colonization and reduced lung function; two of these individuals were pancreatic insufficient while the third was pancreatic insufficient. The fourth individual in this study was an infant and these analyses were not performed (Moya-Quiles MR et al. J. Cyst. Fibros., 2009 Jul;8:280-1). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003473468	SCV004213372	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-12-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001284132	SCV005041130	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	CFTR: PM3:Very Strong, PM2, PM5, PP3, PS3:Supporting
Mayo Clinic Laboratories, Mayo Clinic	RCV001284132	SCV005413799	pathogenic	not provided	2023-12-05	criteria provided, single submitter	clinical testing	PP3, PP5, PM2_moderate, PM3_strong, PS3
Fulgent Genetics, Fulgent Genetics	RCV005042131	SCV005673341	pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2024-02-23	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577469	SCV000679342	not provided	Cystic fibrosis		no assertion provided	literature only
Counsyl	RCV000577469	SCV001132365	likely pathogenic	Cystic fibrosis	2018-10-05	no assertion criteria provided	clinical testing